Oxidative damage of biomolecules, such as proteins, lipids, and nucleic acids, has been implicated in diseases ranging from atherosclerosis to ischemia-reperfusion injury to cancer. For example, a wealth of evidence establishes that enhanced oxidant stress occurs within the artery wall of atherosclerotic vessels. Multiple distinct oxidation products are enriched within human atherosclerotic plaques, as well as low density lipoprotein (LDL) recovered from diseased v. normal human aorta.
The role of oxidation in the pathogenesis of coronary artery disease (CAD) has been questioned because of the failures of multiple prospective intervention trials with antioxidant supplements (e.g., alpha tocopherol (vitamin E)). It should be noted, however, that none of the major antioxidant trials to date concomitantly measured systemic markers of oxidant stress to ensure an effect on the process targeted for intervention (i.e., oxidation). This is particularly relevant since the oxidation pathways known to occur within the human atheroma are in large part not effectively inhibited by alpha tocopherol, the major antioxidant supplement in these trials. Moreover, under certain conditions, pro-rather than anti-oxidant actions for species like alpha tocopherol and ascorbate (vitamin C) have been documented.
Much of what is known about the pathways responsible for oxidative injury within the atherosclerotic vessels has been gained by the detection of stable structurally informative oxidation products that convey information regarding the oxidation pathway(s) responsible for their generation. These pathways have been shown to participate in oxidative conversion of LDL into an atherogenic particle, initiation of lipid peroxidation, consumption of nitric oxide potentially, leading to endothelial dysfunction, and activation of matrix metalloprotease and alternative protease cascades, potentially leading to vulnerable plaque. Remarkably, alpha tocopherol is relatively ineffective in blocking these oxidation pathways.
3-Hydroxymethyl-3-methylglutaryl coenzyme A reductase inhibitors (statins) are recognized as having potential utility in a wide variety of inflammatory and immunological disorders unrelated to their lipid lowering effects. These so called pleiotropic effects of statins are believed to include anti-inflammatory and antioxidant actions. The only published markers for monitoring statin anti-inflammatory action are non-specific markers of inflammation, such as C-Reactive Protein (CRP). The levels of CRP only change minimally in response to statin therapy, and it is widely appreciated that alternative markers are needed to monitor the anti-inflammatory and antioxidant actions of statins.